Throughout the years, the treatment and/or cure of cancer and other diseases has been intensely investigated culminating in a wide range of therapies. Cancer has typically been treated with surgery, radiation and chemotherapy, alone or with various therapies employing drugs, biologic agents, antibodies, radioactive immunconjugates, lymphocytes, macrophages, etc. (sometimes collectively referred to as "drugs" or "agents").
Cancer may be diagnosed by a number of methods and procedures including radiographic scanning of the suspected tissue or organ. One such method includes the gamma scan of an injected dose of a radioactive material such as technetium 99m as discussed in detail below.
The common goal of cancer treatments has been to eliminate or ameliorate cancerous tumors/cells, with minimal toxicity to the normal cells/tissue and without unpleasant or sometimes life-threatening side effects.
The delivery of an anticancer drug or agent may be accomplished in numerous ways, such as by irradiation, injection, etc. The intraarterial infusion of anticancer drugs is a widely used procedure which has been used to produce an increase in local tumor effect while attempting to reduce systemic drug toxicity. In this method of treatment, cytotoxicity within the tumor is dependent on drug concentration and the duration of exposure of the tumor to the drug. Drug concentration within the tumor depends upon the amount of blood flow to the tumor, the intra-tumoral deposition of the drug and the required metabolic uptake of the chemotherapeutic agent. The duration of exposure of the drug to the cancerous tumor relates to the rates of blood flow and drug uptake and elimination. E. Kim, Journal of Nuclear Medicines, Vol. 24, No. 10, p. 966.
Conventional methods of intraarterially providing an anticancer drug by injecting the dosage into an artery supplying the organ suspected of having a neoplasm, result in the drug or agent being quickly removed from the cancerous site due to the circulation of blood and fluids through that organ. T. Kato, et al., Journal of the American Medical Association, Vol. 245, No. 11, p. 1123-1127 (March 1981).
One such conventional cancer therapy utilizes an intraperitoneal or intracavitary injection of a colloidal suspension of the radioactive isotope phosphorous 32, i.e., .sup.32 P, which is commercially available from Mallinckrodt Medical, Inc., St. Louis, Mo. 63134, and sold under the trademark PHOSPHOCOL P 32. PHOSPHOCOL P 32 is a chromic phosphate .sup.32 P suspension with a concentration of up to 185 megabecquerels (5 millicuries) per milliliter and a specific activity of up to 185 megabecquerels (5 millicuries) per milliliter at the time of standardization. PHOSPHOCOL P 32 is supplied as a sterile, nonpyrogenic aqueous solution in a 30% dextrose solution with 2% benzyl alcohol added as a preservative. Each milliliter contains 1 mg sodium acetate. Sodium hydroxide or hydrochloric acid may be present for Ph adjustment.
Phosphorus-32 decays by beta emission with a physical half-life of 14.3 days. The mean energy of the beta particle is 695 keV. D. Kocher, Radioactive Decay Data Tables, DOE/TIC 11026, page 70 (1981). The presence of the radioactive phosphorous in a tumor bearing region is determined by using beta scanning equipment modified to scan "bremsstrahlung" radiation. Since a portion of the injected radioactive phosphorous preferentially binds to the tumor, a radiation scan modified to record filtered "bremsstrahlung" will produce an image of the tumor, while a gamma scan with Technetium 99 will produce an image of non-tumor tissue as discussed below.
Unfortunately, a method of effectively administering the therapeutically effective colloidal phosphorous isotope suspension (and other isotopes) so that the isotope remains in contact with the cancerous tissue (e.g., in solid tumors) for the desired time period in internal organs, has eluded researchers and physicians alike for many years. The amount of time therefore that tumors in internal organs are exposed to the isotope or therapeutic drug or other agent is often less than desirable, since the drug is removed relatively quickly from the cancerous site (i.e., "washed out" or "cleared") into the rest of the body through the circulation. The wash out effect also results in the isotope or drug infiltrating non-cancerous tissue/cells, potentially damaging or destroying those structures. With this complicating limitation, radioactive drugs or agents, as well as some drugs, have not been administered and/or are not successful in achieving desirable results in the treatment by arterial or venous infusion of cancers of internal organs and internal sites.
One attempt to solve this problem utilized a colloidal chromic phosphate (P.sup.32) solution injected into the hepatic artery and portal vein of dogs and man. B. Levine, et al., Cancer, Vol. 10, p. 164-171 (1957). However, the researchers concluded that radioactive colloidal chromic phosphate could not be deposited within intrahepatic malignant tumor tissue, and that almost all of the radioactivity present was present in normal liver tissue. This was due to recirculation of the isotope after failing to remain within the tumor.
The present invention is therefore addressed to partially or totally diminishing the exiting vascular flow of a tumor bearing region to permit an intraarterially supplied agent to remain in contact with the tumor or tumor bearing region and not be immediately eliminated or "washed out" from that region. The present invention accomplishes this goal by the use of macro aggregated proteins such as albumin.
Many prior art methods attempting to achieve the goal of effective and targeted drug delivery have been met with very limited success. One method tried intraarterially infused chemotherapeutic agents in combination with an arterial occlusion to prolong the transit time of the drug through the tumor's vascular bed. The investigators carrying out this method believed that the occlusion prolonged the transit time of the drug through the tumor's vascular bed, thereby increasing the contact time of the drug with the tumor cells. E. Kim, Journal of Nuclear Medicine, Vol. 24, No. 10, p. 966. In these attempts to produce an occlusion, the investigators tried to use a variety of materials such as polyvinyl alcohol, foam particles, gelatin sponge fragments, and stainless steel coils implanted into the patient. In order to visualize or measure the rate of occlusion, the investigators also used the conventional imaging procedure which uses a solution of technetium Tc 99m macro aggregated protein to view the sites by examining the amount of gamma radiation given off by the technetium. However, many of the articles used in that study to produce an occlusion had to be surgically implanted and were therefore less than desirable. In addition, the vasculature of the tumor has not always been accessible.
Prior to the present invention, there has therefore been a long felt need for a simple, easy and fast method of preventing the rapid clearance of therapeutic agents, such as isotopes, radioimmunoconjugates and anticancer drugs, from the desired sites.
The use of technetium 99m macroaggregated albumin solely as an imaging agent is well known in the art. A. Bledin et al., The British Journal of Radiology, Vol. 57, No. 675, p. 197-203 (March 1984); H. Jacobson, et al., Journal of American Medical Association, Topics in Radiology/Nuclear Radiology, Vol. 250, No. 7, p. 941-943 (August 1983); C. Tula, et al., Clinical Nuclear Medicine, Vol. 8, p. 131-132 (March 1983).
Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours. The principal photon that is useful for detection and imaging studies in gamma-2, having a mean%/disintegration of 89.07 and a mean energy level of 140.5 keV.
One prior art technetium imaging kit which is commercially available is the "MPI MAA Kit, Kit for the Preparation of Technetium Tc 99m Albumin Aggregated Injection" which includes radioactive technetium Tc 99m and albumin aggregated protein. This kit is sold as Product No. 44322, by MEDI+PHYSICS, INC., of Arlington Hts., Ill. 60004, and is manufactured by Merck Frosst Canada, Inc. of Kirkland, Quebec, Canada. The product literature accompanying the kit indicates that the kit contains 10 multidose reaction vials which contain the sterile, non-pyrogenic, non-radioactive ingredients necessary to produce technetium Tc 99m albumin aggregated injection for diagnostic use by intravenous injection. Each 10 ml reaction vial contains 2.5 mg of albumin aggregated, 5.0 of albumin human, 0.06 mg (minimum) stannous chloride (maximum stannous and stannic chloride 0.11 mg) and 1.2 mg of sodium chloride. The contents are in a lyophilized form under an atmosphere of nitrogen. Sodium hydroxide or hydrochloric acid is used for pH adjustment. No bacteriostatic preservative is present.
The aggregated particles are formed by denaturation of human albumin in a heating and aggregation process. Each vial contains approximately 4 to 8 million suspended particles. The kit indicates that the average number of particles in a vial is 6 million. By light microscopy, more than 90% of the particles are between 10 and 70 micrometers, while the typical average size is 20 to 40 micrometers; none is greater than 150 micrometers. The Technetium Tc 99m Albumin Aggregated Injection for intravenous use is in its final dosage form when sterile isotonic sodium pertechnetate solution is added to each vial. No less than 90% of the pertechnetate Tc 99m added to a reaction vial is bound to aggregate at preparation time and remains bound throughout the 6 hour lifetime of the preparation.
.sup.99 Technetium is used for three major purposes of scanning. As .sup.99 Technetium colloid, it is a liver scanning agent demonstrating the presence of tumor by the absence of isotopic uptake. .sup.99 Technetium also is used to scan for bony metastasis giving a positive isotopic image. .sup.99 Technetium macroaggregated albumin is used for scanning pulmonary emboli (blood clots) by the absence of the isotope.
Prior to the present invention, there has therefore been a long felt need for a simple, easy and fast method of preventing the rapid clearance of therapeutic agents, such as isotopes, radioimmunoconjugates and anticancer drugs, from the desired sites.
Prior to the present invention, therapeutic agents such as monoclonal antibodies, radiopharmaceuticals and radioactive growth factors were limited in efficacy due to the inability to deposit significant quantities of the agents in cancer, e.g., solid tumor cancers. Carrasquillo, J. A., Radioimmunoscintigraphy with polyclonal or monoclonal antibodies, Zalutsky M (ed.), Antibodies in Radiodiagnosis and Therapy, Boca Raton, Fla., CRC Press, pages 169-198 (1988).
The present invention describes a new technique which, by direct infusion of a blocking material followed by cytotoxic agents into the interstitium, increases tumor deposition of these agents, both experimentally and in clinical application. The clinical technique causes no acute symptoms may be carried out on an out-patient basis, and will allow for a host of new agents to be evaluated for therapeutic efficacy due to the greater tumor concentrations achieved (84-94%) of the infused dose.
Three major physiological factors in cancer have been identified which inhibit significant tumor concentrations of cytotoxic agents. They include elevated interstitial pressure, a large transport distance in the interstitial space of tumors and the tumor's heterogeneous vascular supply. Delivery of novel therapeutic agents in tumors: physiological barriers and strategies, J. National Cancer Institute, Jain, R. K., Vol. 81, pages 570-576 (1989). In addition, the persistence time required for the interaction of cytotoxic agents and the tumor cannot be easily achieved J. National Cancer Institute, Jain, R. K., Vol. 81, pages 570-576 (1989), (see FIGS. 1 and 2). Following intravenous infusion, the circulation causes volumetric dilution and reduces persistence time. This is further complicated by continued recirculation of the agents throughout the body, thus further reducing the opportunity for binding in the tumor.
Accordingly, a need exists for a use of particles such as macro aggregated proteins or peptides in the effective treatment of a variety of diseases and conditions to increase the retention time of the therapeutic agent at a desired treatment site. In addition, a need exists to deliver a therapeutic agent to an organ or other body portion which may not be completely accessible to the vascular injection of the therapeutic agent due, perhaps in part, to tumor growth.